The objective of this proposal is to apply the anti-idiotype (Id) vaccine approach for the therapy of stage III (resected node positive) melanoma patients. Disialoganglioside GD2 is expressed at high density on melanoma cells and will be used as a target for immunotherapy. We have generated a murine monoclonal anti-Id antibody 1A7 (TriGem) which functionally mimics GD2 and acts as a surrogate protein antigen for the ganglioside. In pre-clinical studies, active immunization of mice, rabbits and monkeys with TriGem induced polyclonal IgG anti-GD2 responses and TriGemspecific T cell proliferative responses suggesting the generation of CD4+ T cell help. In previous clinical trials, we have demonstrated that patients with advanced metastatic melanoma and patients with high risk melanoma in the postsurgical adjuvant setting generated active immune responses against GD2 following immunization with TriGem. We demonstrated a predominantly IgG polyclonal humoral immune response with specific binding to purified GD2 and GD2 positive cells that mediated antibody-dependent cellular cytotoxicity (ADCC). The vaccinated patients also demonstrated in vitro T cell proliferative responses in the presence of TriGem. Median survival was 16+ months for 47 patients with advanced disease. Eighty-two percent of 69 patients with stage III disease are alive at a median follow up of 2 years. Twenty-five of the 69 patients with stage III disease were treated with high dose interferon Alfa-2b (HDI) plus TriGem. Immune responses were equivalent or superior to TriGem alone and 96 percent are alive and 80 percent are disease free. Toxicity of TriGem was limited to local reactions at the site of injection with occasional mild fevers. In this project, we will conduct a randomized Phase III clinical trial in which 294 patients with node positive local regional melanoma will be stratified by nodal status (IIIA vs IIIB vs IIIC) and then randomized to treatment with either HDI or HDI plus TriGem. The patients will be observed for immune responses and for clinical outcome. We will continue to test the hypothesis that elicitation of a strong immunologic response will eradicate the residual tumor cells, prevent the dissemination of metastatic disease, and prolong survival in high risk patients in the post-surgical adjuvant setting. To achieve this goal, we have proposed four specific aims. The primaryobjective of this clinical study is to compare the effect of HDI versus HDI plus TriGem on relapse free survival. The secondary objective is to compare the effect on overall survival. The third objective is correlation of the quantitative IgG anti-GD2 response with relapse free and overall survival. The fourth is to monitor toxicity.